Method for improving water solubility of slightly soluble substance

ABSTRACT

It is an object of the present invention to provide a method for improving the solubility of a poorly-soluble substance, which is capable of increasing the solubility of substantially all poorly-soluble substances. This is a method comprising coating the surface of a poorly-soluble substance particle with microparticles of a calcium compound such as calcium phosphate or calcium carbonate, and at least one selected from a pH adjuster and a surfactant, by applying mechanical energy thereto.

TECHNICAL FIELD

The present invention relates to a method for improving the aqueoussolubility of a poorly-soluble substance used in pharmaceuticalproducts, veterinary pharmaceutical products, quasi-drugs, cosmeticproducts, food products, agricultural chemicals, and the like.

BACKGROUND ART

Useful substances have often poor solubility in water in the fields ofpharmaceutical products, veterinary pharmaceutical products,quasi-drugs, cosmetic products, food products, agricultural chemicals,and the like. This restricts the use of useful substances. Thus, it hasbeen desired to develop a method for improving the solubility ofpoorly-soluble useful substances.

Under such circumstances, the present inventors had proposed a methodfor improving the solubility of a poorly-soluble substance, wherein thesurface of the poorly-soluble substance particle is coated by applyingmechanical energy to allow the microparticles of a calcium compound suchas calcium phosphate or calcium carbonate to penetrate into thepoorly-soluble substance particle to improve the solubility (see PatentDocument 1).

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: WO2011/039952

SUMMARY OF THE INVENTION Object to be Solved by the Invention

The above described method for improving the solubility of apoorly-soluble substance by coating the surface of the poorly-solublesubstance particle with the microparticles of a calcium compound such ascalcium phosphate or calcium carbonate can be an extremely useful meansfor increasing the solubility of poorly-soluble substances. However,there has been a case in which the desired solubility cannot necessarilybe obtained, depending on the type of a poorly-soluble substance.

It is an object of the present invention to provide a method forimproving the solubility of a poorly-soluble substance, which is capableof increasing the solubility of substantially all poorly-solublesubstances.

Means to Solve the Object

With regard to the aforementioned method proposed by the presentinventors, the inventors have searched for various additives and havefurther studied regarding modification of the particles ofpoorly-soluble substances, etc. As a result, the inventors have foundthat the dispersibility of a poorly-soluble substance can be improved bycoating the surface of the poorly-soluble substance particle withmicroparticles of a calcium compound such as calcium phosphate orcalcium carbonate, and particularly hydroxyapatite, and also with a pHadjuster and/or a surfactant, by applying mechanical energy thereto, andthus that the solubility of the poorly-soluble substance can beimproved.

In the case of a method using calcium compound microparticles, it isassumed that as soon as a poorly-soluble substance coated with thecalcium compound microparticles is contacted with water, a part ofcrystals of the poorly-soluble substance would be removed together withthe calcium compound microparticles, and the surface area of thepoorly-soluble substance would be thereby increased, and also that smallcalcium compound microparticles, as well as the poorly-solublesubstance, would be in a state in which they are nearly dissolved inwater, and the amount of the poorly-soluble substance dissolved would bethereby improved. Accordingly, it is considered that, by coating thesurface of a poorly-soluble substance particle with calcium compoundmicroparticles and also with a pH adjuster and/or a surfactant accordingto a method comprising applying mechanical energy thereto, the force ofallowing the calcium compound microparticles to compressively adhere tothe surface of the poorly-soluble substance can be increased, and whenthe calcium compound microparticles are removed from the poorly-solublesubstance, its removing action or dispersing action can be maximized.

Specifically, the present invention relates to:

-   (1) a method for producing a substance with improved aqueous    solubility, comprising coating the surface of a poorly-soluble    substance particle with calcium compound microparticles and at least    one selected from a pH adjuster and a surfactant by applying    mechanical energy, to produce the substance with improved aqueous    solubility;-   (2) the method for producing a substance with improved aqueous    solubility according to (1) above, wherein the calcium compound is    calcium phosphate or calcium carbonate;-   (3) the method for producing a substance with improved aqueous    solubility according to (2) above, wherein the calcium phosphate is    hydroxyapatite or tricalcium phosphate;-   (4) the method for producing a substance with improved aqueous    solubility according to any one of (1) to (3) above, wherein at    least 5% of the surface of the poorly-soluble substance particle is    coated with the calcium compound microparticles;-   (5) the method for producing a substance with improved aqueous    solubility according to any one of (1) to (4) above, which is a    method using at least a pH adjuster, wherein the pH adjuster is used    so that the pH of an aqueous solution of the substance with improved    aqueous solubility becomes pH 6 or more;-   (6) the method for producing a substance with improved aqueous    solubility according to any one of (1) to (4) above, which is a    method using at least a surfactant, wherein the amount of the    surfactant used is 1% to 300% by mass with respect to the    poorly-soluble substance;-   (7) the method for producing a substance with improved aqueous    solubility according to any one of (1) to (6) above, wherein the    method of applying mechanical energy is a method involving    mechanical fusion;-   (8) the method for producing a substance with improved aqueous    solubility according to any one of (1) to (6) above, wherein the    method of applying mechanical energy is a method involving    hybridization;-   (9) the method for producing a substance with improved aqueous    solubility according to any one of (1) to (8) above, wherein the    mean particle diameter of the calcium compound microparticles is 100    μm or less;-   (10) the method for producing a substance with improved aqueous    solubility according to (9) above, wherein the mean particle    diameter of the calcium compound microparticles is 50 to 200 nm;-   (11) the method for producing a substance with improved aqueous    solubility according to any one of (1) to (5) and (7) to (10) above,    wherein the pH adjuster is at least one selected from the group    consisting of disodium hydrogen phosphate, L-arginine, sodium    hydrogen carbonate, citric acid, and sodium dihydrogen phosphate;-   (12) the method for producing a substance with improved aqueous    solubility according to any one of (1) to (4) and (6) to (10) above,    wherein the surfactant is sodium dodecyl sulfate; and-   (13) the method for producing a substance with improved aqueous    solubility according to any one of (1) to (12) above, wherein the    poorly-soluble substance is a substance acting as an active    ingredient of any one of a pharmaceutical product, a veterinary    pharmaceutical product, a quasi-drug, a cosmetic product and an    agricultural chemical, or a food additive.

Furthermore, the present invention relates to:

-   (14) a substance with improved aqueous solubility obtained by the    method according to any one of (1) to (13) above;-   (15) a pharmaceutical product, a veterinary pharmaceutical product,    a quasi-drug, a cosmetic product, an agricultural chemical or a food    product, comprising the substance with improved aqueous solubility    according to (14) above; and-   (16) the pharmaceutical product, veterinary pharmaceutical product,    quasi-drug, cosmetic product, agricultural chemical or food product    according to (15) above, which is an aqueous liquid composition.

Effect of the Invention

According to the present invention, the solubility of all poorly-solublesubstances, which are used for pharmaceutical products, veterinarypharmaceutical products, quasi-drugs, cosmetic products, food products,agricultural chemicals, and the like, can be increased. In addition, thepresent invention is advantageous in terms of productivity and costperformance, it is excellent in terms of safety for workers, and it ishighly useful in industrial application.

MODE OF CARRYING OUT THE INVENTION

The method for producing a substance with improved aqueous solubility ofthe present invention is not particularly limited, as long as it is amethod which comprises coating the surface of a poorly-soluble substanceparticle with calcium compound microparticles and at least one selectedfrom a pH adjuster and a surfactant by applying mechanical energythereto. The term “dissolution” is used in the present invention to notonly include a state in which a substance is completely dissolved inwater, but also include a state in which a substance is uniformlydispersed in an aqueous medium and it seems a transparent liquid byvisual observation, such as a solubilized state as a result of micelleformation or the like. It means a state in which the amount of asubstance dissolved can be measured by a test method generally used inthe measurement of the dissolved amount of such a substance.

In the present invention, the surface of a poorly-soluble substanceparticle is coated with calcium compound microparticles and also with apH adjuster and/or surfactant according to a method of applyingmechanical energy thereto. Accordingly, it is considered that the forceof allowing the calcium compound microparticles to compressively adhereto the surface of the poorly-soluble substance can be increased, andwhen the calcium compound microparticles are removed from thepoorly-soluble substance, its removing action or dispersing action canbe maximized.

Moreover, in the case of a poorly-soluble substance exhibiting acidity,since calcium compound microparticles are dissolved in acid, the calciumcompound microparticles need to exhibit their dispersion force withoutbeing completely dissolved, with respect to a decrease in pH occurringupon the dissolution of the poorly-soluble substance. Furthermore, thesolubility of a weak electrolyte such as a poorly-soluble substance ischanged depending on the pH of a solution. Thus, the higher the pH of aweakly acidic compound, the larger the ratio of an ionic form that canbe obtained, and as a result, solubility increases. Accordingly, in thecase of a poorly-soluble substance exhibiting acidity, it is consideredthat the pH is increased by addition of a pH adjuster, so that synergiceffects between the improvement of dissolution by the calcium compoundmicroparticles and the improvement of the solubility of thepoorly-soluble substance itself can be exhibited. Further, in the caseof a poorly-soluble substance exhibiting basicity, it is considered thatthe solubility of a poorly-soluble substance is suppressed because thepH of the coating calcium compound microparticles is basic. In thiscase, the pH of a local portion that is contacted with thepoorly-soluble substance is more important than the pH of a solution asa whole, and it is considered that the effect of improving aqueoussolubility can be further increased by decreasing the pH of a solutioncontacted with the poorly-soluble substance by addition of a pHadjuster. Still further, it is considered that a surfactant is capableof improving the dispersibility of a poorly-soluble substance in waterand of promoting solubilization.

In the method of the present invention in which a pH adjuster is used,with respect to a poorly-soluble substance exhibiting acidity(calcium-coated poorly-soluble substance), a pH adjuster exhibitingstronger basicity can be used, and with respect to a poorly-solublesubstance exhibiting basicity (calcium-coated poorly-soluble substance),a pH adjuster exhibiting stronger acidity can be used. It is preferableto use a pH adjuster such that the pH of an aqueous solution of asubstance with improved aqueous solubility becomes pH 6 or more. That isto say, with respect to an acidic poorly-soluble substance having a lowpH value, it is preferable to add a pH adjuster to a solution such thatthe pH of an aqueous solution of the substance with improved aqueoussolubility becomes at least pH 6. On the other hand, with respect to abasic poorly-soluble substance as well, it is preferable to add a pHadjuster to a solution such that pH of an aqueous solution of thesubstance with improved aqueous solubility does not become extremely lowand that it becomes pH 6 or more. A mechanism of further improvingsolubility by retaining pH 6 or more has not necessarily beenelucidated. It is assumed that if pH is less than 6, the dissolution ofa calcium compound would progress and it would affect the removingaction or dispersing action upon the removal of the calcium compoundfrom a poorly aqueous soluble substance.

Moreover, as described above, since the pH of a local portion that iscontacted with a poorly-soluble substance is more important than the pHof a solution as a whole, when an acidic substance is dissolved, desiredeffects can be obtained even though the pH is not extremely high. It issufficient if a pH adjuster is used such that the pH of an aqueoussolution of a substance with improved aqueous solubility becomes pH 8 orless. Accordingly, it is preferable to use a pH adjuster such that thepH of an aqueous solution of a substance with improved aqueoussolubility becomes pH 6 to 8. Herein, the pH of an aqueous solutionindicates a pH value that is measured 60 minutes after the addition of atarget substance to 50 mL of distilled water in an amount 2 times largerthan the substance dissolved in 360 minutes. More specifically, the pHof an aqueous solution indicates a pH value that is measured accordingto [Dissolution test of poorly-soluble substances] in thebelow-mentioned Examples.

The method of the present invention in which a pH adjuster is used iseffective for poorly-soluble substances having any pH value. The presentmethod is more effective in the case of using a poorly-solublesubstance, regarding which the pH of an aqueous solution containing thecalcium-coated substance is less than 6 or more than 8. The presentmethod is particularly effective in the case of using a poorly-solublesubstance, regarding which the pH of an aqueous solution containing thecalcium-coated substance is less than 5 or more than 9.

In addition, in the method of the present invention in which asurfactant is used, the surfactant is used at a percentage of preferably1% to 300% by mass, and more preferably 10% to 200% by mass, based onthe total mass of a poorly-soluble substance. As the amount of such asurfactant added increases, the effect of improving dissolution becomeshigher. However, taking into consideration toxicity and the like, thesurfactant is used in an amount used in common practice.

Moreover, in the present invention, it is preferable to use a pHadjuster in combination with a surfactant. Since the effect of improvinga dissolved amount by a pH adjuster is different from the effect ofimproving a dissolved amount by a surfactant in terms of action, theeffect of improving solubility can be enhanced by each action.

Specific examples of the coating method of the present inventioninclude: a method which comprises coating the surface of apoorly-soluble substance particle with calcium compound microparticlesby applying mechanical energy thereto, and then coating theaforementioned surface with a pH adjuster and/or a surfactant byapplying mechanical energy thereto (method A); a method which comprisescoating the surface of a poorly-soluble substance particle with a pHadjuster and/or a surfactant by applying mechanical energy thereto, andthen coating the aforementioned surface with calcium compoundmicroparticles by applying mechanical energy thereto (method B); and amethod which comprises coating the surface of a poorly-soluble substanceparticle with a mixture of calcium compound microparticles and a pHadjuster and/or a surfactant by applying mechanical energy thereto(method C). In the present invention, since the particle of apoorly-soluble substance is coated by applying mechanical energy, a partor the entire of calcium compound microparticles, a pH adjuster, and asurfactant is allowed to penetrate into the poorly-soluble substanceparticle, and thereby, the surface of the poorly-soluble substanceparticle can be coated. In the case of the above described method A andmethod B, there is a case in which a substance as a second layer wouldnot reach the particle of the poorly-soluble substance and it wouldpenetrate into a first layer. In the present invention, in order toobtain higher solubility, it is particularly preferable to adopt amethod which comprises coating the surface of a poorly-soluble substanceparticle with a mixture of calcium compound microparticles and a pHadjuster and/or a surfactant by applying mechanical energy thereto(method C).

The calcium compound is preferably a poorly-soluble calcium compoundthat is hardly dissolved in water. Examples of such a compound includecalcium phosphate, calcium carbonate, calcium sulfate, and calciumhydroxide. Of these, calcium phosphate and calcium carbonate arepreferable. These calcium compounds may be used singly or in the form ofa mixture of two or more types.

An example of the calcium phosphate is a calcium phosphate having a Ca/Pratio of 0.8 to 2.0, and preferably having a Ca/P ratio of 1.0 to 2.0.Specific examples of such calcium phosphate include hydroxyapatite,tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate,calcium hydrogen phosphate, calcium pyrophosphate, and calciummetaphosphate. Of these, hydroxyapatite and tricalcium phosphate arepreferable. Moreover, the calcium phosphate may be obtained from thenature, or may also be synthesized by a known method such as a wetmethod or a dry method.

The hydroxyapatite is one type of calcium phosphate, which is a mainingredient of the bone. In general, it is shown as a stoichiometriccomposition represented by Ca₁₀(PO₄)₆(OH)₂. The hydroxyapatite ischaracterized in that it can exhibit properties as hydroxyapatite andcan adopt an apatite structure even if it is a non-stoichiometriccomposition whose Ca/P molar ratio is not 1.67. In the presentinvention, both hydroxyapatite as a stoichiometric composition andhydroxyapatite as a non-stoichiometric composition can be used.Hydroxyapatite having a Ca/P molar ratio of 1.4 to 1.8 is preferablyused.

In general, as methods for synthesizing hydroxyapatite, there arevarious types of synthetic methods such as dry synthesis and wetsynthesis. In the case of the wet synthesis for example, hydroxyapatitecan be obtained by allowing a calcium salt to react with phosphate in anaqueous solution. The Ca/P molar ratio of hydroxyapatite can becontrolled by regulating the mixing ratio of a salt as a raw material orsynthetic conditions. In the wet synthetic method for example, if anaqueous solution is adjusted to be basic using an ammonia water or thelike during the synthesis, the Ca/P molar ratio can be controlled to behigh. On the other hand, if the aqueous solution is adjusted to beneutral or weakly acidic using dilute acid, the Ca/P molar ratio can becontrolled to be low.

The tricalcium phosphate may be either α-Ca₃(PO₄)₂ or β-Ca₃(PO₄)₂. Ofthese, α-Ca₃(PO₄)₂ is preferable because this is a more bioactivematerial. As a method for producing tricalcium phosphate, in general, acalcium source is mixed with a phosphoric acid source at a molar ratioof 3:2, and the mixture is then heated at 1200° C. or higher, so as toobtain an α-type tricalcium phosphate. On the other hand, theaforementioned mixture is heated at 1000° C. or lower, so as to obtainβ-type tricalcium phosphate. A specific example of the tricalciumphosphate that can be used herein is the tricalcium phosphate describedin the Japanese Standards of Food Additives, which contains 98.0% to103.0% of tricalcium phosphate [Ca₃(PO₄)₂] when it is dried. Thistricalcium phosphate described in the Japanese Standards of FoodAdditives is used as an anticaking agent for instant coffee, powderymilk products, condiments, powdered preparations, and the like, or as acalcium source for various types of food products.

The calcium carbonate may be derived from the natural products such ascoral, or may also be derived from synthetic products such as calciumoxide, calcium chloride, calcium peroxide, calcium acetate, etc. Therecan be used the precipitated calcium carbonate described in the JapanesePharmacopoeia, such as calcium carbonate containing 98.5% or more ofcalcium carbonate [CaCO₃] when it is dried, or the calcium carbonatedescribed in the Japanese Standards of Food Additives, such as calciumcarbonate which contains 98.0% to 102.0% of calcium carbonate [CaCO₃]when it is dried. These calcium carbonates are used as agents forimproving antacid action in gastroduodenal ulcer or gastritis, calciumfortifiers for various types of food products, and the like.

The type of the pH adjuster is not particularly limited, as long as itis a powdery agent (microparticles). Examples of the pH adjuster thatcan be used herein include substances used as a stabilizing agent, astabilizer, a plasticizer, a lubricating agent, a lubricant, asolubilizing agent, a solubilizer, a buffering agent, a sweetener, abase agent, a corrigent, a binder, a suspending agent, a suspender, anantioxidant, a brightener, a coating agent, a sustaining agent, amoisturizer, a moisture controlling agent, a filer, an antifoamingagent, an augmenting agent, an antistatic agent, a flavoring agent, anaromatic, a coloring agent, a sugar-coated agent, an isotonizing agent,a softener, an emulsifier, a foaming agent, a skin protective agent, anexcipient, a disperser, a disintegrator, a disintegration aid, afragrance, a desiccant, an antiseptic, a preservative, a soothing agent,a dissolving agent, a dissolution aid, or a fluidizer. In Japan, thosedescribed in Japanese Pharmaceutical Excipients (JPE) are preferable.

Specific examples of the pH adjuster exhibiting acidity include ascorbicacid, L-aspartic acid, aspartame, alginic acid, isocyanuric acid, sodiumedetate, zinc chloride, ammonium chloride, magnesium chloride, cysteinehydrochloride, triethanolamine hydrochloride, histidine hydrochloride,meprylcaine hydrochloride, kaoline, casein, fructose, captan,carbazochrome sodium sulfonate hydrate, carboxymethyl starch sodium,carmellose calcium, xanthan gum, xylitol, citric acid, sodium dihydrogencitrate, disodium citrate, glycyrrhizic acid, dipotassiumglycyrrhizinate, disodium glycyrrhizinate, calcium glycyrrhizinatehydrate, L-glutamine, L-glutamic acid, croscarmellose sodium,crospovidone, aluminum hydroxychloride, light anhydrous silicicacid-containing hydroxypropyl cellulose, crystalline cellulose,crystalline sodium dihydrogen phosphate, gentisic acid ethanolamide,N-cocoyl-arginine ethyl ester-DL-pyrrolidonecarboxylate, succinic acid,monosodium succinate, copolyvidone, choline phosphate, sodiumchondroitin sulfate, potassium dichloroisocyanurate, L-cysteine,tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sucralose,sodium thiomalate, tyloxapol, dextran, corn starch, nicotinamide, lacticacid, aluminum lactate, hydroxypropyl starch, hydroxypropyl cellulose,L-phenylalanine, monosodium fumarate, procaine hydrochloride, powderedcellulose, pectin, boric acid, partially neutralized polyacrylate,polysorbate 20, polysorbate 40, polysorbate 60, macrogol 600, macrogol1000, macrogol 1500, macrogol 1540, macrogol 6000, macrogol 20000,maltose hydrate, malonic acid, anhydrous citric acid, anhydrous sodiumdihydrogen phosphate, methanesulfonic acid, DL-methionine, methylcellulose, sodium N-lauroyl-L-glutamate, L-lysine monohydrochloride,sodium riboflavine phosphate, zinc sulfate hydrate, aluminum sulfate,potassium aluminum sulfate hydrate, oxyquinoline sulfate, DL-malic acid,potassium dihydrogen phosphate, calcium dihydrogen phosphate, and sodiumdihydrogen phosphate monohydrate.

Specific examples of the pH adjuster exhibiting basicity includeL-arginine, tetrasodium edetate, carrageenan, sodium carboxymethylstarch, carmellose sodium, dried sodium sulfite, dried sodium carbonate,xanthan gum, disodium 5′-guanylate, calcium citrate, sodium citratehydrate, trisodium glycyrrhizinate, aluminum magnesium silicate,diatomaceous earth, crystalline cellulose-carmellose sodium, disodiumsuccinate hexahydrate, colloidal hydrous aluminum silicate, sodiumacetate hydrate, calcium bromide, DL-sodium tartrate, potassiumhydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide,sodium hydrogen carbonate, magnesium carbonate, sodium thiosulfatehydrate, sodium desoxycholate, sodium copper chlorophyllin, trometamol,sodium propyl paraoxybenzoate, sodium methyl paraoxybenzoate, potatostarch, calcium pantothenate, L-histidine, hydroxyethyl cellulose,hypromellose, tetrasodium pyrophosphate, heparin sodium, bentonite,borax, sodium polyacrylate, anhydrous sodium citrate, anhydrous sodiumpyrophosphate, anhydrous sodium monohydrogen phosphate, anhydroustrisodium phosphate, meglumine, lauric acid diethanolamide, disodium5′-ribonucleotide, sodium monohydrogen phosphate heptahydrate, trisodiumphosphate, sodium hydrogen phosphate hydrate (disodium hydrogenphosphate), and dipotassium phosphate.

Moreover, a pH adjuster in a neutral range, which exhibits a bufferingaction to the neutral range of pH during the dissolution of a drug, canalso be used. Specific examples of such a pH adjuster in a neutral rangeinclude sodium L-aspartate, ethylene carbonate, calcium disodiumedetate, sodium erythorbate, dried magnesium sulfate, xanthan gum,calcium gluconate hydrate, L-arginine L-glutamate, potassiumL-glutamate, sodium L-glutamate, L-lysine L-glutamate, dihydroxyaluminum amino acetate, D-sorbitol, sodium thiosulfate hydrate, copperchlorophyll, sugar acid calcium, white sugar, and Veegum Neutral.

The type of the surfactant is not particularly limited, as long as it isa powdery agent (microparticles). In Japan, those described in JapanesePharmaceutical Excipients (JPE) are preferable. Examples of thesurfactant include N-cocoyl-L-arginine esterester-DL-pyrrolidonecarboxylate, N-cocoyl-N-methylaminoethyl sulfonatesodium, cholesterol, self-emulsifying glyceryl monostearate, sucrosefatty acid ester, polyoxyl 40 stearate, cetanol, cetomacrogol 1000,sodium dodecylbenzenesulfonate, polyoxyethylene cetyl ether,polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160)polyoxypropylene (30) glycol, glyceryl monostearate, sorbitanmonostearate, N-coconut oil fatty acid acyl-L-arginine-ethylDL-pyrrolidonecarboxylate, sodium dodecyl sulfate (SDS), sodium laurylsulfate, diethanolamide laurate, and sodium lauroyl sarcosinate.

The size of the calcium compound microparticle or the microparticle of apH adjuster and/or a surfactant, which are used in the presentinvention, is preferably smaller than the particle diameter of apoorly-soluble substance. In addition, the smaller the particlediameter, the larger the specific surface area, and as a result, therate of coating the poorly-soluble substance can be enhanced. Thus, theparticle diameter is preferably as small as possible. Specifically, thepresent calcium compound microparticles are, for example, particleshaving a mean particle diameter of preferably 100 μm or less, morepreferably 50 μm or less, further preferably 10 μm or less, andparticularly preferably 1 μm or less. The lower limit of the particlediameter is not particularly limited. It is generally approximately 0.05μm for production reasons. The size of a calcium compound microparticle,or of the microparticle of a pH adjuster and/or a surfactant, to bepenetrated into the poorly-soluble substance particle serving as a core,is more preferably ⅕ or less, and further preferably 1/10 or less, withrespect to the size of the poorly-soluble substance particle because thestate of the penetrated calcium compound microparticle, or of themicroparticle of a pH adjuster and/or surfactant, can be stably retainedwhen the microparticle has the aforementioned size.

The method of finely grinding the calcium compound and the like is notparticularly limited and include a dry method and a wet method, and ageneral dry mill or wet mill can be used, for example. For instance, abead mill, a sand mill, a high-speed impact mill, a high-pressure wetatomizing unit, and the like can be used. Specific examples of the beadmill and sand mill include: Visco Mill manufactured by Aimex Co., Ltd.;Grain Mill manufactured by Asada Iron Works Co., Ltd.; Dyno-Millmanufactured by Sinmaru Enterprises Corp.; Anealler Mill manufactured byMitsui Kozan K. K.; Sand Mill manufactured by Inoue Manufacturing Co.,Ltd.; and Sand Mill manufactured by Kotobuki Engineering & ManufacturingCo., Ltd. An example of the high-speed impact mill isUltra-High-Pressure Homogenizer manufactured by MIZUHO Industrial CO.,LTD. Examples of the high-pressure wet atomizing unit include: Nanomizermanufactured by Yoshida Kikai Co., Ltd.; Atomization Apparatusmanufactured by Sugino Machine Ltd.; and Atomization Apparatusmanufactured by Microfluidics.

In the present invention, as a method of coating a poorly-solublesubstance with such calcium compound microparticles or a pH adjusterand/or a surfactant, a method of applying mechanical energy is applied.This is specifically a method comprising coating a poorly-solublesubstance with calcium compound microparticles and the like by applyingmechanical energy such as physical compression, shearing force or impactforce to allow the microparticles and the like to penetrate into thepoorly-soluble substance particle. Examples of this coating methodinclude a mechanical fusion method and a hybridization method. Morespecific examples of such a coating method include: Mechanofusion System(manufactured by Hosokawa Micron Group), Hybridization System(manufactured by Nara Machinery Co., Ltd.), Theta Composer (manufacturedby Tokuju Corp.), KRYPTRON (manufactured by Kawasaki Heavy Industries,Ltd.), Mechanomill (manufactured by Okada Seiko Co., Ltd.), CF Mill(manufactured by Ube Industries, Ltd.), COMPOSI (manufactured by NipponCoke & Engineering Co., Ltd.), Swing Processor (manufactured by DaltonCo., Ltd.), SFP (manufactured by Powrex Corp.), Cyclomix (manufacturedby Hosokawa Micron Group), Nanomech Reactor [Simoloyer] (J. TEC Ltd.),MAIC (Aveka, Inc.), and Rotating fluidized bed coater (RFBC)(International Publication WO2007/010396).

Moreover, with regard to the amounts of calcium compound microparticlesthat coat the poorly-soluble substance, the surface of the particle ofthe poorly-soluble substance is coated at a percentage of preferably 5%or more, more preferably 60% or more, further preferably 90% or more,and particularly preferably 100%. Coating with a single layer providessufficient effects, although the poorly-soluble substance may also becoated with two or more layers.

Furthermore, it is preferable to coat the poorly-soluble substanceparticle such that the outermost layer thereof is coated with asubstance having high water absorbability. For example, when a pHadjuster or a surfactant is not a substance having high waterabsorbability, the above described method B or method C can be adopted.In the case of adopting the method C, it is preferable that thepoorly-soluble substance be coated with calcium compound microparticlesserving as an outermost layer.

The type of the poorly-soluble substance used in the present inventionis not particularly limited, as long as it is a substance having aproperty that it is hardly dissolved in water. It is a substance havinga solubility (25° C.) of, for example, 10000 ppm or less, 5000 ppm orless, 3000 ppm or less, and 1000 ppm or less. Examples of such apoorly-soluble substance include: a substance acting as an activeingredient for pharmaceutical products, veterinary pharmaceuticalproducts, quasi-drugs, cosmetic products and agricultural chemicals; anda food additive. Synthetic or natural polymeric substances, which aregenerally referred to as resins or rubbers, are not included in thepresent poorly-soluble substance. The size of the poorly-solublesubstance is not particularly limited. Its mean particle diameter ispreferably 0.5 to 2000 μm, more preferably 1 to 200 μm, and furtherpreferably 5 to 50 μm.

The poorly-soluble drug used in the present invention is a drug that is“sparingly soluble,” “slightly soluble,” “very slightly soluble,” and“practically insoluble,” which are defined in the JapanesePharmacopoeia. The present poorly-soluble drug may have any dosage formof an oral preparation for internal application, an injection, apreparation for local administration, etc. Examples of such apoorly-soluble drug include an antitumor agent, an antibiotic, anantipyretic analgesic, an antihyperlipidemic agent, an antibacterialagent, a sedative hypnotic, a tranquilizer, an antiepileptic agent, anantidepressant, a gastrointestinal agent, an allergic diseasetherapeutic agent, an antihypertensive agent, a drug forarteriosclerosis, a blood circulation promoting agent, an antidiabeticagent, a hormonal agent, a fat-soluble vitamin, an antiandrogen agent, acardiotonic drug, a drug for arrhythmia, a drug for diuresis, a localanesthetic, an anthelminthic, an antiarrhythmic agent, an anticoagulant,an antihistamic agent, an antimuscarinic agent, an antimycobacterialagent, an immunosuppressive agent, an antithyroid agent, an antiviralagent, an anxiolytic agent, an astringent, a β-adrenoreceptor blocker,an agent exerting inotropic action on cardiac muscle, a contrast medium,corticosteroid, a cough suppressing agent, a diagnostic agent, adiagnostic imaging agent, a diuretic, a dopamine agonist, a hemostaticagent, a lipid adjuster, a muscle relaxer, a parasympathetic drug,thyrocalcitonin and biphosphonate, prostaglandin, a radiopharmaceuticalagent, sex hormone, a stimulant, an appetite suppressing agent, asympathetic agent, a thyroid drug, a vasodilator, and xanthene.

Specific examples of the antitumor agent include HER2 inhibitors(heterocyclic compounds described in WO01/77107 and the like),melphalan, taxol, dacarbazine, doxorubicin hydrochloride, bleomycinhydrochloride, carmofur, methotrexate, enocitabine, etoposide,5-fluorouracil, mitoxantrone, mesna, dimesna, aminoglutethimide,tamoxifen, acrolein, cisplatin, carboplatin, cyclophosphamide,lomustine, carmustine, cyclophosphamide, busulphan, para-aminosalicylicacid, mercaptopurine, tegafur, azathioprine, vinblastine sulfate,mitomycin C, ciclosporin, L-asparaginase, and ubenimex.

Examples of the antibiotic include amikacin, dibekacin, gentamycin,bacitracin, penicillin, cephalexin, tetracycline, streptomycin,nystatin, erythromycin, fradiomycin sulfate, chloramphenicol,cefmetazole, and tolnaftate.

Examples of the antipyretic analgesic include aspirin, aspirin aluminum,aminopyrine, phenacetin, mefenamic acid, flufenamic acid, flufenamicacid aluminum, tolfenamic acid, acemetacin, indomethacin, alclofenac,diclofenac, ibuprofen, ibuprofenpiconol, oxyphenbutazone,phenylbutazone, ketophenylbutazone, clofezone, tiaramide hydrochloride,ketoprofen, diclofenac sodium, sulindac, naproxen, fenbufen,flurbiprofen, fenprofen, bufexamac, mepirizole, perisoxal citrate,glafenine, bucolome, pentazocine, metiazinic acid, protizinic acid,pranoprofen, fenoprofen calcium, piroxicam, feprazone, fentiazac,bendazac, dimethylisopropylazulene, glycyrrhetic acid, bufexamac,salicylic acid, acetaminophen, methyl salicylate, glycol salicylate,bucolome, benzydamine, tialamide, tinoridine, ethenzamide, tenoxicam,chlortenoxicam, clidanac, naproxen, glycyrrhizin, glycyrrhetic acid,azulene, camphor, thymol, l-menthol, sasapyrine, alclofenac, diclofenac,suprofen, loxoprofen, diflunisal, tiaprofenic acid, oxaprozin, andfelbinac.

Examples of the antihyperlipidemic agent include clinofibrate,clofibrate, fenofibrate, bezafibrate, cholestyramine, soysterol,tocopherol nicotinate, nicomol, niceritrol, probucol, simvastatin,colestimide, and elastase.

Examples of the antibacterial agent include ofloxacin, ciprofloxacinhydrochloride, tosufloxacin tosilate, norfloxacin, lomefloxacinhydrochloride, pazufloxacin, rokitamycin, cefpodoxime proxetil,roxithromycin, midecamycin acetate, cefatrizine, josamycin propionate,and fosfomycin or a salt thereof.

Examples of the sedative hypnotic include barbital, amobarbital,amobarbital sodium, phenobarbital, phenobarbital sodium, secobarbitalsodium, pentobarbital calcium, hexobarbital, triclofos,bromovalerylurea, glutethimide, methaqualone, perlapine, nitrazepam,estazolam, flurazepam hydrochloride, flunitrazepam, and estazolam.

Examples of the tranquilizer include diazepam, lorazepam, and oxazolam.

Examples of the antiepileptic agent include phenyloin, phenobarbital,carbamazepine, primidone, phenacemide, ethylphenacemide, ethotoin,phensuximide, nitrazepam, and clonazepam.

Examples of the antidepressant include imipramine, noxiptiline, andphenelzine.

Examples of the gastrointestinal agent include aldioxa, irsogladinemaleate, metoclopramide, cimetidine, famotidine, omeprazole,lansoprazole, enprostil, gefarnate, teprenone, sulpiride, trepibutone,oxethazain, and sucralfate.

Examples of the allergic disease therapeutic agent include clemastinefumarate, cyproheptadine hydrochloride, fexofenadine hydrochloride,ebastine, mequitazine, diphenhydramine, methdilazine, clemizole, andmethoxyphenamine.

Examples of the antihypertensive agent include alacepril, nicardipinehydrochloride, delapril hydrochloride, captopril, cilnidipine,felodipine, barnidipine hydrochloride, efonidipine hydrochloride,amlodipine besylate, benidipine hydrochloride, nisoldipine, manidipinehydrochloride, nitrendipine, nilvadipine, trandolapril, valsartan,candesartan cilexetil, urapidil, carvedilol, prazosin hydrochloride,bunazosin hydrochloride, doxazosin mesilate, reserpine, methyldopa,guanabenz acetate, deserpidine, meptame, and meptamate.

Examples of the drug for arteriosclerosis include clofibrate,simfibrate, elastase, soysterol, and nicomol.

Examples of the blood circulation promoting agent include tocopherolacetate, benzyl nicotinate, tolazoline, verapamil, caffeine,cyclandelate, acetylcholine, and tocopherol nicotinate.

Examples of the antidiabetic agent include tolbutamide, glibenclamide,gliclazide, troglitazone, epalrestat, buformin, and metformin.

Examples of the hormonal agent include dexamethasone, dexamethasoneacetate, betamethasone, betamethasone valerate, betamethasonedipropionate, beclometasone dipropionate, prednisolone, prednisolonevalerate, prednisolone acetate, methylprednisolone, methylprednisoloneacetate, hydrocortisone, hydrocortisone acetate, hydrocortisone acetatepropionate, amcinonide, triamcinolone, triamcinolone acetonide,fluocinolone acetonide, hexestrol, methimazole, estriol, estrioltripropionate, clobetasone acetate, clobetasol propionate, fluocinonide,testosterone propionate, testosterone enanthate, fluoxymesterone,drostanolone propionate, estradiol benzoate, estradiol propionate,estradiol valerate, ethinylestradiol, mestranol, estriol benzoatediacetate, fluorometholone, fludroxycortide, diflucortolone valerate,halcinonide, progesterone, hydroxyprogesterone caproate, pregnanediol,medroxyprogesterone acetate, dimethisterone, norethisterone,allylestrenol, gestonorone caproate, and oxendolone.

Examples of the antiandrogen agent include oxendolone, allylestrenol,chlormadinone acetate, gestonorone caproate, osaterone acetate,flutamide, and bicalutamide.

Examples of the cardiotonic drug include digoxin, digotoxin, andubidecarenone.

Examples of the drug for arrhythmia include pindolol, nadolol,bopindolol malonate, arotinolol hydrochloride, atenolol, lidocaine,propafenone hydrochloride, amiodarone hydrochloride, disopyramide, andcarteolol hydrochloride.

Examples of the drug for diuresis include polythiazid, spironolactone,chlortalidone, triamteren, hydrochlorothiazide, and furosemide.

Examples of the local anesthetic include dibucaine hydrochloride, ethylaminobenzoate, procaine hydrochloride, lidocaine, tetracainehydrochloride, lidocaine hydrochloride, T-Cain, benzocaine, benzylalcohol, pramoxine hydrochloride, quatacaine hydrochloride, butanicainehydrochloride, piperocaine hydrochloride, and chlorobutanol.

Examples of the substance used in cosmetic products or quasi-drugsinclude methyl cinnamate, ethyl cinnamate, dl-α-tocopherol acetate,α-tocopherol (vitamin E), trichlorocarbanilide, eugenol, isoeugenol,ethyl methyl phenylglycidate, geranyl acetate, piperonal, hexyl laurate,ionone, cinnamyl acetate, decyl oleate, terpinyl acetate, triazine,anilide, benzophenone, triazole, cinnamide, sulfonated benzoimidazole,carotene, piroctone olamine, minoxidil, phytosteside, tocopherolnicotinate, ethinyl estradiol, polyporusterone, ecdysteroids, andvarious types of perfumes.

Examples of the substance used in food and drink products includeL-ascorbyl stearate, benzoic acid, ionone, isoeugenol, ergocalciferol(vitamin D₂), eugenol, butyl parahydroxybenzoate, isopropylparahydroxybenzoate, β-carotene, citronellyl formate, cholecalciferol(vitamin D₃), cinnamyl acetate, phenethyl acetate, ethyl cinnamate,dibutylhydroxytoluene, allyl hexanoate, propyl gallate, methyl β-methylketone, folic acid, riboflavine tetrabutyrate, lecithin, anddl-α-tocopherol.

Examples of the agricultural chemical include poorly-solubleagricultural chemical active ingredients having insecticidal action,germicidal action, herbicidal action, plant growth regulatory and otheractions, such as a substance having a solubility in water (25° C.) of1000 ppm or less.

Specifically, examples of the poorly-soluble insecticidal substanceinclude abamectin, acrinathrin, amitraz, azadirachtin, azamethiphos,azinphos-methyl, azocyclotin, ethofenprox, ethylthiometon, chlorpyrifosmethyl, bensultap, bifenthrin, bromopropylate, buprofezin, carbaryl,chlorfenapyr, chlorfenson, chlorfluazuron, clofentezine, coumaphos,diazinon, cycroprothrin, cyfluthrin, β-cyfluthrin, cypermethrin,α-cypermethrin, θ-cypermethrin, deltamethrin, diafehthiuron, dicofol,diflubenzuron, carbosulfan, endosulfan, esfenvalerate, etoxazole,fenazaquin, fenbutatin oxide, fenoxycarb, fenpyroximate, fipronil,fluazuron, flucycloxuron, flufenoxuron, flubendiamide, fenthion,halofenozide, hexaflumuron, hexythiazox, hydramethylnon, metaflumizone,lufenuron, methiocarb, methoxychlor, milbemycin, novaluron,pentachlorophenol, pyridaben, rotenone, sulfluramid, tebufenozide,tebufenpyrad, tebupirimfos, teflubenzuron, tetrachlorvinphos,tetradifon, thiodicarb, benfuracarb, tralomethrin, tolfenpyrad,triflumuron, trimethacarb, furathiocarb, and bendiocarb.

Examples of the poorly-soluble germicidal substance includeazoxystrobin, isoprothiolane, benalaxyl, benomyl, bitertanol,bromuconazole, captafol, captan, carpropamide, carbendazim,chinomethionate, chlorothalonil, chlozolinate, cyprodinil,dichlofluanid, diclofen, diclomezine, dicloran, diclocymet,diethofencarb, dimethomorph, diniconazole, dithianon, tiadinil,epoxiconazole, famoxadone, fenarimol, fenbuconazole, fenfuram,fenpiclonil, fentin, fluazinam, fludioxonil, fluoroimide,fluquinconazole, flusulfamide, flutolanil, folpet, hexachlorobenzene,hexaconazole, imibenconazole, ipconazole, iprodione, kresoxim-methyl,manzeb, maneb, mepanipyrim, mepronil, metconazole, metiram, nickelbis(dimethyldithiocarbamate), nuarimol, oxine copper, oxolinic acid,pencycuron, phthalide, procymidone, propineb, quintozene, sulfur,tebuconazole, tecloftalam, tecnazene, thifluzamide, thiophanete-methyl,thiram, tolclofos-methyl, tolylfluanide, triadimefon, triadimenol,triazoxide, triforine, triticonazole, vinclozolin, zineb, and ziram.

Examples of the poorly-soluble herbicidal substance include azafenidin,thenylchlor, bifenox, sulfentrazone, pyraflufen-ethyl,flumiclorac-pentyl, flumioxazin, aclonifen, atrazine, indanofan,bensulfuron methyl, benzofenap, bromobutide, bromofenoxim,chlomethoxyfen, chlorbromuron, chlorimuron ethyl, chlornitrofen,chlortoluron, chlorthal-dimethyl, clomeprop, dymron, desmedipham,dichlobenil, diflufenican, dimefuron, dinitramine, diuron,ethametsulfuron methyl, traiziflam, fenoxaprop-ethyl, flamprop-methyl,flazasulfuron, flumetsulam, fluthiacet-methyl, flupoxam, fluridone,flurtamone, oxaziclomefone, isoproturon, isoxaben, isoxapyrifop,lactofen, lenacil, linuron, mefenacet, methabenzthiazuron, metobenzuron,naproanilide, neburon, norflurazon, oryzalin, oxadiazon, oxyfluorfen,phenmedipham, prodiamine, prometryn, propazine, propyzamide,pyrazolynate, pyrazosulfuron-ethyl, pyributicarb, quinclorac, quizalofopethyl, rimsulfuron, siduron, simazine, terbuthylazine, terbutryn,thiazopyr, tralkoxydim, and trietazine.

Examples of the poorly-soluble plant growth regulatory substance include6-benzylaminopurine, cyclanilide, flumetralin, forchlorfenuron,inabenfide, 2-(1-naphtyl)acetamide, paclobutrazol, n-phenylphthalamidicacid, thidiazuron, and uniconazole.

The substance with improved aqueous solubility obtained by theproduction method of the present invention can be used by mixing it intopharmaceutical products, veterinary pharmaceutical products,quasi-drugs, cosmetic products, agricultural chemicals, food products,and the like. The forms of the pharmaceutical products, veterinarypharmaceutical products, quasi-drugs, cosmetic products, agriculturalchemicals, and food products are not particularly limited. The forms maybe either solid compositions such as a tablet, granule or powder, oraqueous liquid compositions containing water. As a result of theimprovement of solubility according to the present invention, asubstance, which has not sufficiently exhibited effects due to its poorsolubility, can exhibit the effects.

EXAMPLES

1. [Preparation of Coating Agent]

A. [Preparation of Hydroxyapatite Microparticles]

A phosphoric acid aqueous solution in a 30 wt % concentration was addeddropwise to a calcium hydroxide suspension under stirring, until theCa/P ratio became 1.67. The thus generated gelatinous substance was leftat a room temperature for 1 day, so as to age it. Thereafter, thisgelatinous substance was filtrated with a glass filter, and theremaining substance was then dried in the air at 100° C. The resultantwas ground with a mixer, so as to obtain hydroxyapatite.

Such hydroxyapatite was suspended in water to prepare a 20% suspension.This suspension was then ground employing Dino Mill (ECM-PILOT,manufactured by Willy A. Baechofen AG Machinenfabrik Basel) using 0.3-mmzirconia beads. Particle size distribution was measured every 30minutes, and the grinding was terminated at the time point in whichalmost no change was observed in terms of particle size, therebyobtaining hydroxyapatite microparticles.

B. [Preparation of pH Adjuster and Surfactant]

A pH adjuster and a surfactant were each crushed in a mortar, and theywere then passed through a 150-μm mesh sieve. The resultants were usedin experiments.

2. [Preparation of Substance with Improved Aqueous Solubility]

A. [Coating of Poorly-Soluble Substance with HydroxyapatiteMicroparticles Using Mechanofusion System]

Using Mechanofusion System AMS-MINI-GMP (manufactured by Hosokawa MicronGroup), a poorly-soluble substance was coated with hydroxyapatitemicroparticles.

A poorly-soluble substance and hydroxyapatite microparticles were placedinto a Mechanofusion System Device while changing the ratio between thepoorly-soluble substance and the hydroxyapatite microparticles. Theywere placed in the device to a total amount of 90 g/once, andthereafter, a coating treatment was carried out. During the coatingtreatment, the jacket portion of the device was cooled with alcohol, sothat the temperature of the portion became 20° C. or lower. Moreover, inorder to prevent the rotation load from exceeding 2.0 A, the coatingtreatment was carried out at a rotation number of 1,250 to 4,000 rpm for15 to 60 minutes. In the case of products, which could be subjected to acoating treatment at a rotation number of 4,000 rpm, the coatingtreatment was carried out for 15 minutes. On the other hand, in the caseof products whose rotation load exceeded 2.0 A, and consequently, therotation number became 4,000 rpm or less, a coating treatment time wasincreased due to the rotation number. Thus, a coating treatment wascarried out at the fewest rotation number (1,250 rpm) for 60 minutes asthe longest coating treatment time.

The coated substance was recovered, and thereafter, ground pH adjusterand/or surfactant were added to the recovered substance in an amount of1/100 to 3 times the amount of the poorly-soluble substance. Theobtained mixture was subjected to Mechanofusion Device again, so as toproduce a final pharmaceutical preparation. Thereby, there was obtaineda pharmaceutical preparation, in which the outermost layer of apharmaceutical preparation formed by coating a poorly-soluble substancewith hydroxyapatite microparticles was coated with a pH adjuster and/ora surfactant.

B. [Coating of Poorly-Soluble Substance with HydroxyapatiteMicroparticles According to Hybridization System]

Using Hybridization System NHS-1 (manufactured by Nara Machinery Co.,Ltd.), a poorly-soluble substance was coated with calcium compoundmicroparticles.

A mixture that had previously been prepared by mixing a poorly-solublesubstance with hydroxyapatite microparticles was placed in theHybridization System, while changing the ratio between thepoorly-soluble substance and the hydroxyapatite microparticles. Theywere placed in the system to a total amount of 100 g/once, andthereafter, a coating treatment was carried out at 3,000 rpm for 5minutes.

The resultant was recovered, and thereafter, ground pH adjuster and/orsurfactant were added thereto in an amount of 1/100 to 3 times theamount of the poorly-soluble substance. The obtained mixture was againsubjected to Hybridization System, so as to produce a finalpharmaceutical preparation. Thereby, there was obtained a pharmaceuticalpreparation, in which the outermost layer of a pharmaceuticalpreparation formed by coating a poorly-soluble substance withhydroxyapatite microparticles was coated with a pH adjuster and/or asurfactant.

3. [Dissolution Test of Poorly-soluble Substances]

A poorly-soluble substance coated with calcium compound microparticles(a substance with improved aqueous solubility) and a test solution (50mL) were placed in a 50-mL screw cap centrifuge tube made of glass. Frominitiation of the test, the mixed solution was stirred with a stirrerhaving a length of 15 mm. The rotation number of the stirrer was 120rpm, and all of the tests were conducted in a thermostat at 37±0.5° C.Two types of test solutions, namely, distilled water and 2nd fluid fordisintegration test (pH 6.8) of the Japanese Pharmacopoeia were used. Assuch 2nd fluid for disintegration test of the Japanese Pharmacopoeia, asolution prepared by diluting the 10-fold concentration solution ofKanto Kagaku Co., Ltd. with distilled water was used. With regard to theamount of a substance with improved aqueous solubility used in thedissolution test, a preliminary test was carried out on each substancewith improved aqueous solubility several times according to the abovedescribed method, and the amount of the substance with improved aqueoussolubility used in the dissolution test was defined as an amountapproximately two times the amount of the substance with improvedaqueous solubility dissolved for 360 minutes.

A comparative test was carried out in the same manner as that describedabove, with the exception that, instead of a substance with improvedaqueous solubility coated with hydroxyapatite microparticles and with apH adjuster and/or a surfactant, a poorly-soluble substance or the likewas used in the same amount as the substance with improved aqueoussolubility.

1 mL of the solution was sampled in an Eppendorf centrifuge tube, 1, 3,10, 30, 60, 180 and 360 minutes after initiation of the test. The thussampled solution was centrifuged at 12,000 rpm for 5 minutes.Thereafter, the substance with improved aqueous solubility andhydroxyapatite microparticles, which had not been dissolved in thesolution, were removed. In the case of the comparative test, thepoorly-soluble substance or the like, which had not been dissolved inthe solution, was removed. An aliquot of this supernatant wasimmediately frozen. The frozen sample was freeze-dried, and it was thenused as a sample in the measurement of the amount of the substance withimproved aqueous solubility, which had been dissolved in the testsolution. The dissolved poorly-soluble substance was measured mainlyusing a dual wavelength absorption photometer.

3-1. [Dissolved Amounts of Poorly-soluble Substances after DissolutionTest for 360 Minutes]

1. Tolbutamide

TABLE 1 Coating agent Dissolved Coating Particle Coating amount methodIngredient diameter Additive rate Dissolution test medium (μg/ml)Example 1-1 Mechanofusion Hydroxyapatite 100 nm Disodium 100% Distilledwater 7101.4 System hydrogenphosphate Second disintegration 5250.4 1/10test medium Example 1-2 Mechanofusion Hydroxyapatite 100 nm Disodium100% Distilled water 8502.0 System hydrogenphosphate Seconddisintegration 6098.6 1/5 test medium Example 1-3 MechanofusionHydroxyapatite  50 nm Disodium 100% Distilled water 8792.7 Systemhydrogenphosphate Second disintegration 7883.4 1/5 test medium Example1-4 Mechanofusion Hydroxyapatite 100 nm L-Arginine 1/5 100% Distilledwater 8391.2 System Second disintegration 5766.8 test medium Example 1-5Mechanofusion Hydroxyapatite 100 nm SDS1/5 100% Distilled water 8678.0System Second disintegration 6319.3 test medium Example 1-6Mechanofusion Hydroxyapatite 100 nm Disodium 100% Distilled water 7498.7System hydrogenphosphate Second disintegration 5685.3 1/10 SDS1/10 testmedium Comparative Mechanofusion Hydroxyapatite 100 nm Not used 100%Distilled water 2584.0 Example 1-1 System Second disintegration 4913.4test medium Comparative Mechanofusion Not used Disodium 100% Distilledwater 133.3 Example 1-2 System hydrogenphosphate Second disintegration532.1 1/5 test medium Comparative Mechanofusion Not used L-Arginine 1/5100% Distilled water 768.4 Example 1-3 System Second disintegration1792.4 test medium Comparative Mechanofusion Not used SDS1/5 100%Distilled water 302.5 Example 1-4 System Second disintegration 1862.3test medium Comparative Tolbutamide Distilled water 68.6 Example 1-5Second disintegration 2429.1 test medium2. Bezafibrate

TABLE 2 Dissolved Coating Coating agent Coating amount method IngredientGrinding Additive rate Dissolution test medium (μg/ml) Example 2-1Hybridization Hydroxyapatite 100 nm Disodium 100% Distilled water 7426.9System hydrogenphosphate Second disintegration 7012.8 1/100 test mediumExample 2-2 Hybridization Hydroxyapatite 100 nm Disodium 100% Distilledwater 13498.4 System hydrogenphosphate Second disintegration 11743.61/10 test medium Example 2-3 Hybridization Hydroxyapatite   10 μmDisodium 100% Distilled water 9193.2 System hydrogenphosphate Seconddisintegration 9046.5 1/5 test medium Example 2-4 HybridizationHydroxyapatite 100 nm Disodium 100% Distilled water 14741.2 Systemhydrogenphosphate Second disintegration 12127.5 1/5 test medium Example2-5 Hybridization Hydroxyapatite 100 nm Disodium  50% Distilled water13702.5 System hydrogenphosphate Second disintegration 11171.8 1/5 testmedium Example 2-6 Hybridization Hydroxyapatite 100 nm Disodium  10%Distilled water 11856.2 System hydrogenphosphate Second disintegration10572.2 1/5 test medium Example 2-7 Hybridization Hydroxyapatite  50 nmDisodium 100% Distilled water 12101.2 System hydrogenphosphate Seconddisintegration 11116.2 1/5 test medium Example 2-8 HybridizationHydroxyapatite 100 nm Disodium 100% Distilled water 8363.0 Systemhydrogenphosphate Second disintegration 3876.7 3/1 test medium Example2-9 Hybridization Hydroxyapatite 100 nm L-Arginine 1/5  10% Distilledwater 16703.3 System Second disintegration 12298.4 test medium Example2-10 Hybridization Hydroxyapatite 100 nm Sodium 100% Distilled water19659.9 System hydrogencarbonate Second disintegration 15898.4 1/5 testmedium Example 2-11 Hybridization Hydroxyapatite 100 nm SDS1/5 100%Distilled water 18239.1 System Second disintegration 15137.5 test mediumComparative Hybridization Hydroxyapatite 100 nm Not used 100% Distilledwater 3440.3 Example 2-1 System Second disintegration 6538.0 test mediumComparative Mixing Hydroxyapatite 100 nm Not used 100% Distilled water101.2 Example 2-2 Second disintegration 2254.3 test medium ComparativeHybridization Not used Disodium 100% Distilled water 181.3 Example 2-3System hydrogenphosphate Second disintegration 1180.0 1/5 test mediumComparative Hybridization Not used Sodium 100% Distilled water 944.1Example 2-4 System hydrogencarbonate Second disintegration 4154.3 1/5test medium Comparative Hybridization Not used SDS1/5 100% Distilledwater 1012.0 Example 2-5 System Second disintegration 9984.8 test mediumComparative Bezafibrate Distilled water 13.2 Example 2-6 Seconddisintegration 3096.6 test medium3. Famotidine

TABLE 3 Dissolved Coating Coating agent Coating amount method IngredientGrinding Additive rate Dissolution test medium (μg/ml) Example 3-1Mechanofusion Hydroxyapatite 100 nm Citric 100% Distilled water 11365.1System acid 1/5 Second disintegration 10710.8 test medium Example 3-2Mechanofusion Hydroxyapatite 100 nm SDS1/5 100% Distilled water 2380.6System Second disintegration 4929.7 test medium ComparativeMechanofusion Hydroxyapatite 100 nm Not used 100% Distilled water 1671.5Example 3-1 System Second disintegration 2698.4 test medium ComparativeMechanofusion Not used Citric 100% Distilled water 956.5 Example 3-2System acid 1/5 Second disintegration 1468.1 test medium ComparativeMechanofusion Not used SDS1/5 100% Distilled water 1580.0 Example 3-3System Second disintegration 1809.2 test medium Comparative FamotidineDistilled water 1497.4 Example 3-4 Second disintegration 2410.4 testmedium4. Trimethoprim

TABLE 4 Dissolved Coating Coating agent Coating amount method IngredientGrinding Additive rate Dissolution test medium (μg/ml) Example 4-1Hybridization Hydroxyapatite 100 nm Citric 100% Distilled water 10144.4System acid 1/5 Second disintegration 13265.3 test medium ComparativeHybridization Hydroxyapatite 100 nm Not used 100% Distilled water 1212.6Example 4-1 System Second disintegration 2532.6 test medium ComparativeHybridization Not used Citric 100% Distilled water 806.9 Example 4-2System acid 1/5 Second disintegration 1985.0 test medium ComparativeTrimethoprim Distilled water 656.3 Example 4-3 Second disintegration1321.9 test medium5. Probucol

TABLE 5 Dissolved Coating Coating agent Coating amount method IngredientGrinding Additive rate Dissolution test medium (μg/ml) Example 5-1Mechanofusion Hydroxyapatite 100 nm Disodium 100% Distilled water 561.5System hydrogenphosphate Second disintegration 332.4 1/5 test mediumComparative Mechanofusion Hydroxyapatite 100 nm Disodium 100% Distilledwater 289.1 Example 5-1 System and hydrogenphosphate Seconddisintegration 180.6 Mixing(* 1/5 test medium Comparative ProbucolDistilled water 9.7 Example 5-2 Second disintegration 28.0 test medium*Probucol was coated with hydroxyapatite using Mechanofusion System, anddisodium hydrogen phosphate was then mixed therein.6. Sulpiride

TABLE 6 Dissolved Coating Coating agent Coating amount method IngredientGrinding Additive rate Dissolution test medium (μg/ml) Example 6-1Mechanofusion Hydroxyapatite 100 nm Citric 100% Distilled water 12814.7System acid 1/100 Second disintegration 18099.7 test medium Example 6-2Mechanofusion Hydroxyapatite 100 nm Citric 100% Distilled water 35293.4System acid 1/5 Second disintegration 38081.1 test medium Example 6-3Mechanofusion Hydroxyapatite 100 nm Citric 100% Distilled water 18186.7System acid 3/1 Second disintegration 23748.5 test medium Example 6-4Mechanofusion Hydroxyapatite 100 nm SDS1/100 100% Distilled water 6695.6System Second disintegration 9735.7 test medium Example 6-5Mechanofusion Hydroxyapatite 100 nm SDS1/5 100% Distilled water 6923.0System Second disintegration 13619.7 test medium Example 6-6Mechanofusion Hydroxyapatite 100 nm SDS3/1 100% Distilled water 22631.4System Second disintegration 27321.3 test medium ComparativeMechanofusion Hydroxyapatite 100 nm Not used 100% Distilled water 1144.8Example 6-1 System Second disintegration 6459.8 test medium ComparativeMechanofusion Not used Citric 100% Distilled water 1733.0 Example 6-2System acid 1/5 Second disintegration 5700.0 test medium ComparativeMechanofusion Not used SDS1/5 100% Distilled water 2425.0 Example 6-3System Second disintegration 3746.2 test medium Comparative SulpirideDistilled water 715.8 Example 6-4 Second disintegration 6866.1 testmedium7. Lidocaine

TABLE 7 Dissolved Coating Coating agent Coating amount method IngredientGrinding Additive rate Dissolution test medium (μg/ml) Example 7-1Mechanofusion Hydroxyapatite 100 nm Citric 100% Distilled water 29934.4System acid 1/5 Second disintegration 35102.5 test medium ComparativeMechanofusion Hydroxyapatite 100 nm Not used 100% Distilled water 4528.8Example 7-1 System Second disintegration 8760.0 test medium ComparativeMechanofusion Not used Citric 100% Distilled water 3582.6 Example 7-2System acid 1/5 Second disintegration 6360.1 test medium ComparativeLidocaine Distilled water 3248.6 Example 7-3 Second disintegration5469.0 test medium8. Alacepril

TABLE 8 Dissolved Coating Coating agent Coating amount method IngredientGrinding Additive rate Dissolution test medium (μg/ml) Example 8-1Mechanofusion Hydroxyapatite 100 nm Disodium 100% Distilled water26119.0 System hydrogenphosphate Second disintegration 27527.2 1/5 testmedium Example 8-2 Mechanofusion Hydroxyapatite 100 nm Disodium 100%Distilled water 31636.7 System hydrogenphosphate Second disintegration32384.9 1/4 test medium Comparative Alacepril Distilled water 996.5Example 8-1 Second disintegration 2548.2 test medium9. Erythromycin

TABLE 9 Dissolved Coating Coating agent Coating amount method IngredientGrinding Additive rate Dissolution test medium (μg/ml) Example 9-1Mechanofusion Hydroxyapatite 100 nm Citric 100% Distilled water 25648.9System acid 1/5 Second disintegration 21844.7 test medium ComparativeErythromycin Distilled water 846.1 Example 9-1 Second disintegration6044.7 test medium10. Haloperidol

TABLE 10 Dissolved Coating Coating agent Coating amount methodIngredient Grinding Additive rate Dissolution test medium (μg/ml)Example 10-1 Hybridization Hydroxyapatite 100 nm Citric 100% Distilledwater 562.7 System acid 1/5 Second disintegration 148.6 test mediumComparative Haloperidol Distilled water 13.1 Example 10-1 Seconddisintegration 48.9 test medium3-2. [Dissolution Time and Dissolved Amount]1. TolbutamideDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 11 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 1-1 Disodium hydrogenphosphate 6704.6 6852.3 6925.97441.6 7339.2 6735.4 7101.4 1/10 + 100 nm HAP Example 1-2 Disodiumhydrogenphosphate 7087.3 7936.0 8375.1 8201.9 8391.2 8344.4 8502.0 1/5 +100 nm HAP Example 1-3 Disodium hydrogenphosphate 7057.9 7507.7 8036.58160.2 8320.0 8514.3 8792.7 1/5 + 50 nm HAP Example 1-4 L-Arginine 1/5 +100 nm HAP 8646.2 8646.7 7654.3 8085.7 8281.3 8206.4 8391.2 Example 1-5SDS1/5 + 100 nm HAP 4349.4 6817.6 7650.9 7769.1 8061.2 8096.9 8678.0Example 1-6 Disodium hydrogenphosphate 5711.7 7004.1 7327.2 7795.47188.8 7314.1 7498.7 1/10 + SDS1/10 + 100 nm HAP Comparative 100 nm HAP2114.6 2421.2 2592.4 2591.9 2559.5 2574.2 2584.0 Example 1-1 ComparativeDisodium hydrogenphosphate 105.7 122.1 120.6 131.8 135.8 131.9 133.3Example 1-2 1/5 Comparative L-Arginine 1/5 27.47 139.6 1352.9 1451.8963.8 838.6 768.4 Example 1-3 Comparative SDS1/5 591.6 265.6 384.1 248.7402.5 271.1 302.5 Example 1-4 Comparative — 48.8 49.3 51.3 56.6 50.552.9 68.6 Example 1-5Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 12 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 1-1 Disodium hydrogenphosphate 3565.5 4545.7 5122.95020.9 5111.2 5291.2 5250.4 1/10 + 100 nm HAP Example 1-2 Disodiumhydrogenphosphate 4286.1 5122.4 6100.4 6192.9 6005.6 6125.2 6098.6 1/5 +100 nm HAP Example 1-3 Disodium hydrogenphosphate 7990.5 6127.2 7111.87786.1 8171.6 7721.9 7883.4 1/5 + 50 nm HAP Example 1-4 L-Arginine1/5+100 nm HAP 3475.7 5015.5 6141.8 6110.3 5602.3 5749.3 5766.8 Example1-5 SDS1/5 + 100 nm HAP 2530.3 4384.8 5171.2 5493.5 5496.8 5563.4 6319.3Example 1-6 Disodium hydrogenphosphate 2975.1 4814.9 5513.8 5579.85461.1 5639.1 5685.3 1/5 + SDS1/5 + 100 nm HAP Comparative 100 nm HAP3603.0 3915.4 4265.2 4428.8 4554.5 4907.2 4913.4 Example 1-1 ComparativeDisodium hydrogenphosphate 525.4 475.1 495.7 522.9 447.3 480.8 532.1Example 1-2 1/5 Comparative L-Arginine 1/5 4.1 53.7 960.2 1084.2 1289.62249.2 1792.4 Example 1-3 Comparative SDS1/5 1426.8 1493.2 1584.9 2048.71803.4 1732.1 1862.3 Example 1-4 1000.1 Comparative — 637.3 1597.22041.9 2141.1 2449.4 2432.9 2429.1 Example 1-52. BezafibrateDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 13 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 2-1 Disodium hydrogenphosphate 4737.3 5876.1 6713.07541.3 7586.6 7418.3 7426.9 1/100 +100 nm HAP Example 2-2 Disodiumhydrogenphosphate 13217.0 15062.8 15145.3 15844.6 15564.2 15120.313498.4 1/10+100 nm HAP Example 2-3 Disodium hydrogenphosphate 4636.48858.2 9102.6 9060.9 8963.1 9137.1 9193.2 1/5 + 10 μm HAP Example 2-4Disodium hydrogenphosphate 17967.4 15876.7 16846.8 16067.0 16028.115617.9 14741.2 1/5 + 100 nm HAP Example 2-5 Disodium hydrogenphosphate6256.9 10918.7 13350.3 13610.5 13443.7 12776.5 13702.5 1/5 + 100 nm HAP50% Example 2-6 Disodium hydrogenphosphate 8323.2 10646.9 13714.012353.8 12176.9 12438.6 11856.2 1/5 + 100 nm HAP 10% Example 2-7Disodium hydrogenphosphate 11379.8 12048.4 12414.6 12314.5 12269.412228.2 12101.2 1/5 + 50 nm HAP Example 2-8 Disodium hydrogenphosphate12228.2 6070.3 6648.1 6950.0 7682.6 7745.1 8363.0 3/1 + 100 nm HAPExample 2-9 L-Arginine 1/5 + 100 nm HAP 10840.7 14993.9 18099.3 18051.118020.0 17792.8 16703.3 Example 2-10 Sodium hydrogencarbonate 9297.810413.7 12546.4 14638.3 18502.6 19699.7 19659.9 1/5 + 100 nm HAP Example2-11 SDS1/5 + 100 nm HAP 9504.9 13499.3 17515.4 16393.7 16303.5 18451.518239.1 Comparative 100 nm HAP 2758.5 2941.9 3161.9 3336.4 3289.5 3392.23440.3 Example 2-1 Comparative 100 nm HAP(Mixing) 55.5 78.0 81.3 86.086.1 97.1 101.2 Example 2-2 Comparative Disodium hydrogenphosphate 137.9146.5 166.3 169.4 171.9 178.7 181.3 Example 2-3 1/5 Comparative Sodiumhydrogencarbonate 53.0 119.7 491.6 587.0 734.1 868.4 944.1 Example 2-41/5 Comparative SDS1/5 975.4 993.9 1027.4 900.6 957.8 1096.5 1012.0Example 2-5 Comparative — 10.4 11.6 10.9 11.9 12.3 12.9 13.2 Example 2-6Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 14 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 2-1 Disodium hydrogenphosphate 4211.0 5587.1 7230.76592.2 7278.1 6956.5 7012.8 1/100 + 100 nm HAP Example 2-2 Disodiumhydrogenphosphate 12093.5 13293.2 13272.6 13367.0 13197.8 12777.911743.6 1/10 + 100 nm HAP Example 2-3 Disodium hydrogenphosphate 6016.88271.5 8833.7 8695.7 8957.4 8830.8 9046.5 1/5 + 10 μm HAP Example 2-4Disodium hydrogenphosphate 13713.6 14009.3 14225.5 14026.1 13727.012809.1 12127.5 1/5 + 100 nm HAP Example 2-5 Disodium hydrogenphosphate6606.4 9820.1 10783.5 10760.5 11134.4 11360.2 11171.8 1/5 + 100 nm HAP50% Example 2-6 Disodium hydrogenphosphate 8198.1 10217.0 11683.710868.4 10727.5 10904.3 10572.2 1/5 + 100 nm HAP 10% Example 2-7Disodium hydrogenphosphate 10298.0 10901.0 11256.1 11263.8 10808.511082.6 11116.2 1/5 + 50 nm HAP Example 2-8 Disodium hydrogenphosphate8708.1 5416.7 4150.6 3734.3 3510.0 3328.8 3876.7 3/1 + 100 nm HAPExample 2-9 L-Arginine 1/5 + 100 nm HAP 9550.0 11264.5 13296.1 12841.713123.6 12817.2 12298.4 Example 2-10 Sodium hydrogencarbonate 8616.710460.1 12709.6 12239.0 12363.7 15308.2 15898.4 1/5 + 100 nm HAP Example2-11 SDS1/5 + 100 nm HAP 9409.0 11134.8 14379.2 15139.0 14282.8 15520.015137.5 Comparative 100 nm HAP 4840.4 5420.0 5773.4 5840.2 5976.7 6107.36538.0 Example 2-1 Comparative 100 nm HAP (Mixing) 1754.3 1864.8 2229.62267.6 2224.5 2282.7 2254.3 Example 2-2 Comparative Disodiumhydrogenphosphate 850.7 920.8 1108.1 1152.0 1174.0 1170.1 1180.0 Example2-3 1/5 Comparative Sodium hydrogencarbonate 706.8 1036.8 2704.9 3285.63458.7 3753.2 4154.3 Example 2-4 1/5 Comparative SDS1/5 5724.4 8390.58781.7 9118.3 9124.5 8958.0 9984.8 Example 2-5 Comparative — 805.12552.5 2866.5 2942.6 2965.5 3031.4 3096.6 Example 2-63. FamotidineDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 15 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 3-1 Citric acid 1/5 7688.1 10183.6 11246.5 11673.111584.5 11519.7 11365.1 100 nm HAP Example 3-2 SDS1/5 905.7 1412.12018.2 2294.1 2470.4 2555.6 2380.6 100 nm HAP Comparative 100 nm HAP1080.2 1269.9 1616.6 1834.6 1819.8 1778.1 1671.5 Example 3-1 ComparativeCitric acid 1/5 402.2 363.0 415.4 915.3 850.3 983.5 956.5 Example 3-2Comparative SDS1/5 777.7 1011.1 1646.6 1606.8 1712.6 1761.2 1580.0Example 3-3 Comparative — 1162.9 1502.6 1416.8 1566.8 1565.8 1509.81497.4 Example 3-4Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 16 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 3-1 Citric acid 1/5 6106.9 8806.8 9955.0 10655.3 10742.810784.9 10710.8 100 nm HAP Example 3-2 SDS1/5 1084.6 3248.8 4208.14902.0 4960.1 5020.2 4929.7 100 nm HAP Comparative 100 nm HAP 1943.52409.8 2648.0 2658.9 2690.2 2657.9 2698.4 Example 3-1 Comparative Citricacid 1/5 1696.9 2761.1 1745.7 1787.6 1568.8 1592.7 1468.1 Example 3-2Comparative SDS1/5 1161.5 1500.7 1775.2 1895.9 1818.2 1845.2 1809.2Example 3-3 Comparative — 1980.2 2286.6 2541.7 2600.9 2667.9 2509.72410.4 Example 3-44. TrimethoprimDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 17 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 4-1 Citric acid 1/5 10546.6 11358.0 10853.1 10612.111559.5 10403.0 10144.4 100 nm HAP Comparative 100 nm HAP 1085.3 1186.41208.2 1196.1 1209.9 1225.9 1212.6 Example 4-1 Comparative Citric acid1/5 867.5 1036.6 756.3 812.1 907.9 750.2 806.9 Example 4-2 Comparative —354.6 531.0 685.0 677.9 671.8 672.0 656.3 Example 4-3Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 18 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 4-1 Citric acid 1/5 10960.3 12969.8 13896.0 14411.113778.2 13081.5 13265.3 100 nm HAP Comparative 100 nm HAP 2389.3 2532.82756.7 2698.8 2606.8 2532.8 2532.6 Example 4-1 Comparative Citric acid1/5 1880.1 2192.6 2596.1 2264.9 2361.8 2600.2 1985.0 Example 4-2Comparative — 807.8 1160.4 1291.7 1344.0 1324.8 1296.5 1321.9 Example4-35. ProbucolDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 19 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 5-1 Disodium hydrogenphosphate 88.9 115.1 339.7 550.8462.5 649.3 561.5 1/5 100 nm HAP Comparative Disodium hydrogenphosphate223.1 211.3 244.8 254.8 257.8 277.7 289.1 Example 5-1 1/5 100 nm HAPComparative — 0.7 2.7 3.7 6.1 7.6 8.3 9.7 Example 5-2Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 20 Elution time (min) Example No. Coating ingredient 1 3 10 30 60180 360 Example 5-1 Disodium hydrogenphosphate 35.9 55.8 180.1 163.7379.4 616.5 332.4 1/5 100 nm HAP Comparative Disodium hydrogenphosphate111.1 132.8 142.1 157.1 158.5 173.8 180.6 Example 5-1 1/5 100 nm HAPComparative — 4.7 14.9 19.9 21.2 21.8 26.8 28.0 Example 5-26. SulpirideDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 21 Example Coating Elution time (min) No. ingredient 3 10 30 120360 Example 6-1 Citric acid 1/100 12877.9 12597.2 12425.1 12607.012814.7 100 nm HAP Example 6-2 Citric acid 1/5 29950.1 34620.2 34483.935514.1 35293.4 100 nm HAP Example 6-3 Citric acid 3/1 11590.8 10562.611248.7 11693.6 18186.7 100 nm HAP Example 6-4 SDS1/100 6970.6 6946.66985.9 6336.5 6695.6 100 nm HAP Example 6-5 SDS1/5 6494.7 6917.6 7185.66998.4 6923.0 100 nm HAP Example 6-6 SDS3/1 22841.0 22791.6 22667.022421.8 22631.4 100 nm HAP Comparative 100 nm HAP 1146.0 1204.8 1084.81173.1 1144.8 Example 6-1 Comparative Citric acid 1/5 2028.2 1750.42069.3 2060.1 1733.0 Example 6-2 Comparative SDS1/5 2402.6 2416.2 2390.22421.4 2425.0 Example 6-3 Comparative — 555.2 772.8 803.2 724.9 715.8Example 6-4Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 22 Example Coating Elution time (min) No. ingredient 3 10 30 120360 Example 6-1 Citric acid 1/100 18433.8 18076.0 19386.8 18655.318099.7 100 nm HAP Example 6-2 Citric acid 1/5 32715.2 35731.4 36896.738452.6 38081.1 100 nm HAP Example 6-3 Citric acid 3/1 19070.5 14546.711739.1 19157.5 23748.5 100 nm HAP Example 6-4 SDS1/100 9999.1 9821.79667.8 10128.6 9735.7 100 nm HAP Example 6-5 SDS1/5 9781.1 11062.013110.6 13485.1 13619.7 100 nm HAP Example 6-6 SDS3/1 23446.0 24541.425241.3 30004.4 27321.3 100 nm HAP Comparative 100 nm HAP 5538.8 5098.05944.4 6170.0 6459.8 Example 6-1 Comparative Citric acid 1/5 5804.05445.8 5640.1 5523.4 5700.0 Example 6-2 Comparative SDS1/5 3203.0 3992.33928.0 3997.8 3746.2 Example 6-3 Comparative — 5873.2 6995.7 6751.47206.2 6866.1 Example 6-47. LidocaineDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 23 Example Coating Elution time (min) No. ingredient 3 10 30 180360 Example 7-1 Citric acid 1/5 25916.0 28885.7 26856.3 27951.2 29934.4100 nm HAP Comparative 100 nm HAP 2545.8 2849.5 3764.3 4090.5 4528.8Example 7-1 Comparative Citric acid 1/5 2253.5 2419.1 2850.8 3225.23582.6 Example 7-2 Comparative — 1681.4 2204.3 2246.2 2919.3 3248.6Example 7-3Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 24 Example Coating Elution time (min) No. ingredient 3 10 30 180360 Example 7-1 Citric acid 1/5 25130.2 25237.1 26434.5 27018.1 35102.5100 nm HAP Comparative 100 nm HAP 8860.1 9028.3 8977.9 8765.0 8760.0Example 7-1 Comparative Citric acid 1/5 2400.8 4230.3 5190.9 5566.36360.1 Example 7-2 Comparative — 1873.3 2931.4 4039.8 5485.0 5469.0Example 7-38. AlaceprilDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 25 Example Coating Elution time (min) No. ingredient 3 10 30 120360 Example 8-1 Disodium 28634.4 23227.2 23692.2 24879.0 26119.0hydrogenphosphate 1/5 100 nm HAP Example 8-2 Disodium 34213.2 27170.928093.5 29257.2 31636.7 hydrogenphosphate 1/4 100 nm HAP Comparative —526.2 805.6 931.2 994.9 996.5 Example 8-1Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 26 Example Coating Elution time (min) No. ingredient 3 10 30 120360 Example 8-1 Disodium hydrogenphosphate 26630.5 27702.2 30248.530328.3 27527.2 1/5 100 nm HAP Example 8-2 Disodium hydrogenphosphate30525.2 30598.9 34879.5 34327.3 32384.9 1/4 100 nm HAP Comparative —2311.1 2514.7 2525.0 2588.4 2548.2 Example 8-19. ErythromycinDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 27 Example Coating Elution time (min) No. ingredient 3 10 30 120360 Example 9-1 Citric acid 1/5 20911.5 22571.1 22154.7 23818.3 25648.9100 nm HAP Comparative — 635.0 861.6 944.7 927.7 846.1 Example 9-1Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 28 Example Coating Elution time (min) No. ingredient 3 10 30 120360 Example 9-1 Citric acid 1/5 15564.0 16605.5 17082.5 18728.2 21844.7100 nm HAP Comparative — 2556.3 4984.2 5103.6 5904.1 6044.7 Example 9-110. HaloperidolDissolution Test Using Water Dissolved Amount (μg/ml)

TABLE 29 Example Coating Elution time (min) No. ingredient 3 10 30 120360 Example 10-1 Citric acid 1/5 1000.9 814.7 560.4 592.4 562.7 100 nmHAP Comparative — 8.2 10.0 11.3 12.8 13.1 Example 10-1Dissolution Test Using 2nd Fluid for Disintegration Test DissolvedAmount (μg/ml)

TABLE 30 Example Coating Elution time (min) No. ingredient 3 10 30 120360 Example 10-1 Citric acid 1/5 214.1 303.5 352.6 583.5 148.6 100 nmHAP Comparative — 23.9 35.6 45.2 50.1 48.9 Example 10-1

In addition, the pH of an aqueous solution after the passage of 60minutes in each of the above described Examples, in which distilledwater was used, is shown below.

The pH values of poorly-soluble substances and poorly-soluble substancescoated with coating agents

TABLE 31 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 1-1 Tolbutamide 6.7 100 nm 100 Disodium —hydrogenphosphate 1/10 Example 1-2 Tolbutamide 6.8 100 nm 100 Disodium —hydrogenphosphate 1/5 Example 1-3 Tolbutamide 6.7  50 nm 100 Disodium —hydrogenphosphate 1/5 Example 1-4 Tolbutamide 6.9 100 nm 100 L-Arginine1/5 — Example 1-5 Tolbutamide — 100 nm 100 — SDS1/5 Example 1-6Tolbutamide — 100 nm 100 Disodium SDS1/10 Comparative Tolbutamide 6.6100 nm 100 hydrogenphosphate — Example 1-1 1/10 Comparative Tolbutamide6.4 — — Disodium — Example 1-2 hydrogenphosphate 1/5 ComparativeTolbutamide 6.2 — — L-Arginine 1/5 — Example 1-3 Comparative Tolbutamide— — — — SDS1/5 Example 1-4 Comparative Tolbutamide 4.3 — — — — Example1-5

TABLE 32 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 2-1 Bezafibrate 6.3 100 nm 100 Disodium —hydrogenphosphate 1/100 Example 2-2 Bezafibrate 6.4 100 nm 100 Disodium— hydrogenphosphate 1/10 Example 2-3 Bezafibrate 6.2   10 μm 100Disodium — hydrogenphosphate 1/5 Example 2-4 Bezafibrate 6.4 100 nm 100Disodium — hydrogenphosphate 1/5 Example 2-5 Bezafibrate 6.4 100 nm  50Disodium — hydrogenphosphate 1/5 Example 2-6 Bezafibrate 6.2 100 nm  10Disodium — hydrogenphosphate 1/5 Example 2-7 Bezafibrate 6.4 50 nm 100Disodium — hydrogenphosphate 1/5 Example 2-8 Bezafibrate 7.8 100 nm 100Disodium — hydrogenphosphate 3/1 Example 2-9 Bezafibrate 6.7 100 nm  10L-Arginine 1/5 — Example 2-10 Bezafibrate 7.1 100 nm 100 Sodium —hydrogencarbonate 1/5 Example 2-11 Bezafibrate — 100 nm 100 — SDS1/5Comparative Bezafibrate 6.0 100 nm 100 — — Example 2-1 ComparativeBezafibrate 5.8 100 nm 100 — — Example 2-2 Mixing ComparativeBezafibrate 6.2 — — Disodium — Example 2-3 hydrogenphosphate 1/5Comparative Bezafibrate 6.5 — — Sodium — Example 2-4 hydrogencarbonate1/5 Comparative Bezafibrate — — — — SDS1/5 Example 2-5 ComparativeBezafibrate 4.3 — — — — Example 2-6

TABLE 33 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 3-1 Famotidine 6.3 100 nm 100 Citric acid 1/5 —Example 3-2 Famotidine — 100 nm 100 — SDS1/5 Comparative Famotidine 9.3100 nm 100 — — Example 3-1 Comparative Famotidine 5.5 — — Citric acid1/5 — Example 3-2 Comparative Famotidine — — — — SDS1/5 Example 3-3Comparative Famotidine 8.4 — — — — Example 3-4

TABLE 34 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 4-1 Trimethoprim 6.3 100 nm 100 Citric acid 1/5 —Comparative Trimethoprim 9.1 100 nm 100 — — Example 4-1 ComparativeTrimethoprim 5.9 — — Citric acid 1/5 — Example 4-2 ComparativeTrimethoprim 8.4 — — — — Example 4-3

TABLE 35 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 5-1 Probucol 9.1 100 nm 100 Disodium —hydrogenphosphate 1/5 Comparative Probucol 9.2 100 nm 100 Disodium —Example 5-1 hydrogenphosphate 1/5 Comparative Probucol 5.4 — — — —Fxample 5-2

TABLE 36 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 6-1 Sulpiride 8.9 100 nm 100 Citric acid 1/100 —Example 6-2 Sulpiride 7.1 100 nm 100 Citric acid 1/5 — Example 6-3Sulpiride 6.2 100 nm 100 Citric acid 3/1 — Example 6-4 Sulpiride — 100nm 100 — SDS1/100 Example 6-5 Sulpiride — 100 nm 100 — SDS1/5 Example6-6 Sulpiride — 100 nm 100 — SDS3/1 Comparative Sulpiride 9.5 100 nm 100— — Example 6-1 Comparative Sulpiride 6.6 — — Citric acid 1/5 — Example6-2 Comparative Sulpiride — — — — SDS1/5 Example 6-3 ComparativeSulpiride 9.3 — — — — Example 6-4

TABLE 37 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 7-1 Lidocaine 7.4 100 nm 100 Citric acid 1/5 —Comparative Lidocaine 9.8 100 nm 100 — — Example 7-1 ComparativeLidocaine 6.8 — — Citric acid 1/5 — Example 7-2 Comparative Lidocaine9.7 — — — — Example 7-3

TABLE 38 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 8-1 Alacepril 5.9 100 nm 100 Disodium —hydrogenphosphate 1/5 Example 8-2 Alacepril 6.2 100 nm 100 Disodium —hydrogenphosphate 1/4 Comparative Alacepril 2.9 — — — — Example 8-1

TABLE 39 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 9-1 Erythromycin 6.2 100 ml 100 Citric acid 1/5 —Comparative Erythromycin 9.6 — — — — Example 9-1

TABLE 40 Particle Coating Poorly- pH at 60 diameter rate by pH adjustorSurfactant soluble minutes after of HAP HAP ratio to poorly- ratio topoorly- substance dissolution (μm) (%) soluble substance solublesubstance Example 10-1 Haloperidol 5.6 100 nm 100 Citric acid 1/5 —Comparative Haloperidol 8.1 — — — — Example 10-1

Industrial Applicability

The substance with improved aqueous solubility produced by the presentinvention can be used for pharmaceutical products, veterinarypharmaceutical products, quasi-drugs, cosmetic products, food products,agricultural chemicals, and the like.

The invention claimed is:
 1. A method of making a coated substancecomprising: providing an active substance with poor water solubility;providing hydroxyapatite microparticles; providing microparticles of apH adjuster or surfactant as a powder with a particle diameter of 150 μmor less; applying mechanical energy to a combination of said activesubstance and said hydroxyapatite microparticles to form a recoveredsubstance; applying mechanical energy to a combination of said recoveredsubstance and said microparticles of a pH adjuster or surfactant toproduce a coated substance, wherein the microparticles of the pHadjuster or surfactant are present in an amount of 1/100 to 3 times theamount of the poorly soluble substance; and wherein the coated substancehas improved water solubility as compared with the poorly water solublesubstance by itself.
 2. The method of claim 1, wherein the amount of thesurfactant used is 1% to 300% by mass with respect to the poorly watersoluble substance.
 3. The method of claim 1, wherein the method ofapplying mechanical energy to the combination of said active substanceand said hydroxyapatite microparticles to form a recovered substance isa method involving mechanical fusion.
 4. The method of claim 1, whereinthe method of applying mechanical energy to the combination of saidactive substance and said hvdroxvapatite microparticles to form arecovered substance is a method involving hybridization.
 5. The methodof claim 1, wherein the mean particle diameter of the hydroxyapatitemicroparticles is 100 μm or less.
 6. The method of claim 5, wherein themean particle diameter of the calcium compound microparticles is 50 to200 nm.
 7. The method of claim 1, wherein the pH adjuster is selectedfrom the group consisting of disodium hydrogen phosphate, L-arginine,sodium hydrogen carbonate, citric acid, and sodium dihydrogen phosphate.8. The method of claim 1, wherein the surfactant is sodium dodecylsulfate.
 9. The method of claim 1, wherein the poorly water solublesubstance is selected from the group consisting of a pharmaceuticalactive agent, a veterinary pharmaceutical a cosmetic, an agriculturalchemical, and a food additive.
 10. A method of claim 1, wherein thepoorly water soluble substance is selected from the group consisting oftolbutamide, bezafibrate, famotidine, trimethoprim, probucol, sulpiride,lidocaine, alacepril, erythromycin, and haloperidol.
 11. The method ofclaim 1, wherein the method of applying mechanical energy to thecombination of said recovered substance and said microparticles of a pHadjuster or surfactant to produce a coated substance is a methodinvolving hybridization.
 12. The method of claim 1, wherein the methodof applying mechanical energy to the combination of said recoveredsubstance and said microparticles of a pH adjuster or surfactant toproduce a coated substance is a method involving mechanical fusion. 13.The method of claim 1, wherein the method of applying mechanical energyto the combination of said recovered substance and said microparticlesof a pH adjuster or surfactant to produce a coated substance is a methodinvolving mechanical fusion or hybridization.
 14. The method of claim 1,wherein the method of applying mechanical energy to the combination ofsaid active substance and said hydroxyapatite microparticles to form arecovered substance is a method involving mechanical fusion orhybridization.